Clobazam, FRISIUM®

• FRISIUM®

• Benzodiazepines
• Anti-Epileptics

• Tablets 10 mg

• Epilepsy: Adjunctive therapy in patients with epilepsy who are not adequately stabilized with their current anticonvulsant therapy.

Pharmacodynamics:

• Mechanism of Action: The exact mechanisem of action is unknown. Clobazam is a 1,5-benzodiazepine with anticonvulsant properties >>> involve potentiation of GABAergic (gamma-Aminobutyric acid ) neurotransmission resulting from greater binding at the benzodiazepine site of the GABA receptor >>> resulting in a decrease in the firing rate of critical neurons in many regions of the brain.

Pharmacokinetics:

• Absorption: Fast absorption, at least 87% absorbed after orally used. Maximum plasma concentration: 222 to 709 ng/ml after 0.25 to 4 hours.
• Distribution: highly lipophilic and distributes rapidly throughout the body ( Fat and Gray matter). plasma protein binding of Clobazam and N- desmethylclobazam is approximately 80-90% and 70% respectively.
• Metabolism: Active metabolite => N-desmethylclobazam. Primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6
• Excretion: 90% Urine. (Half-life of N-desmethylclobazam = mean 42 hours)

1. Adults:

• Initial dose: 5-15 mg/day ( Do a gradual increase)
• Maximum dose 80 mg/day

2. Children from 2 to 16 years:

• Initial dose 5 mg/day (Do a gradual increase at 5-day intervals)
• Maximum dose: of 40 mg/day

3. Infants ≤ 2 years:

• Initial dose:5-1 mg/kg/day.

4. Elderly: Due to decreased organ function in elderly patients, lower initial doses and gradual dose increments are recommended and patients should be monitored for responsiveness and adverse events.

5. CYP2C19 Poor metabolizers: In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased:

• Starting dose: lowest initial recommended dose and dose (titration should proceed slowly- half the maximum dose described-).
• Maximum dose: (depending on the age group) may be started on day 21.

6. Hepatic Impairment:

• Starting dose: lowest initial recommended dose and dose (titration should proceed slowly- half the maximum dose described-).
• Maximum dose: (depending on the age group) may be started on day 21.

1. Clobazam is weak CYP3A4 (Cytochrome P-450) inducer:

• Possible decrease in dosage of other medications especially Oral Contraceptive Pills in concomitatnt use with Clobazam! >>> Dose adjustment may be necessary.

2. Carbamazepine, phenytoin, phenobarbital, and valproate >>> decrease the blood level of Clobazam >>> dose adjustment may be necessary.

3. Diphenylhydantoin >>> decrease the blood level of Clobazam

4. Fluconazole, fluvoxamine, ticlopidine, Omeprazole (Moderate- Stong Cytochrome P-450 inhibitors) >>> Increase the dose of Clobazam

5. Alcohol >>> increase plasma clobazam levels by approximately 50%

6. Other central nervous system depressant drugs

7. Lithium: Mutually potentiating effect

8. Narcotic Analgesics: Possible euphoria may be enhanced

9. Muscle relaxants and nitrous oxide >>> The effects may be enhanced

Most common:

1. Drowsiness
2. Dizziness
3. Fatigue

Less Common:

1. Blood and lymphatic system disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
2. Eye disorders: Double vision, nystagmus
3. Gastrointestinal disorders: Dry mouth, constipation, loss of appetite, nausea, weight gain, increased appetite, vomiting, abdominal distention
4. General disorders and administration site conditions: Unsteadiness of gait and other motor functions, fatigue, sedation leading to tiredness and sleepiness, especially at the beginning of treatment and when higher doses are used, slowing of reaction time, drowsiness, slow or indistinct speech, irritability, hypothermia
5. Immune system disorders: Hypersensitivity
6. Investigations: Hepatic enzyme increased
7. Infections and infestations: Pneumonia
8. Musculoskeletal and connective tissue disorders: Muscle weakness, frequent muscle spasms
9. Nervous system disorders: Altered state of consciousness, anterograde amnesia, somnolence, lethargy hyporesponsive to stimuli, disorientation, confusion, headaches, tremor, fine tremor of the fingers, dysarthria, psychomotor hyperactivity
10. Renal and urinary disorders: Urinary retention
11. Psychiatric disorders: Suicidal behaviour and ideation, psychotic reactions, hallucination, delusion, acute agitational states, anxiety, emotional disorder, flat affect, aggressiveness, anger, fits of rage, restlessness, difficulty falling asleep or sleeping through, insomnia, nightmare, loss of libido
12. Serious skin reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
13. Respiratory, thoracic and mediastinal disorders: Respiratory distress, respiratory depression, aspiration pneumonia, cough

1. Known hypersensitivity to Clobazam or to any ingredient in the formulation.
2. Myasthenia gravis (risk of aggravation of muscle weakness)
3. Narrow angle glaucoma
4. Any history of drug or alcohol dependence (increased risk of development of dependence)
5. Severe respiratory insufficiency
6. Sleep apnoea syndrome (risk of deterioration)
7. Severe impairment of liver function (risk of precipitating Hepatic encephalopathy)

Pregnancy: Category C

Lactation: Not recommended in nursing mother.

1. The efficacy of FRISIUM in adults aged 65 and over has not been established >>> Use with caution!

2. FRISIUM is contraindicated in patients with Myasthenia Gravis. In patients with pre-existing muscle weakness or with spinal or cerebellar ataxia, special observation is required and a dose reduction may be necessary.

3. Additive effects are to be expected if FRISIUM (Clobazam) is combined with alcohol or drugs with central nervous system depressant effects. >>> Concomitant consumption of alcohol can increase the serum levels of FRISIUM by 50%. >>> Recommend not drinking alcohol while taking Clobazam!

4. Avoid driving or working with dangerous operating machineries while taking Clobazam due to sedative effect.

5. Physical and psychological dependence are known to occur in persons taking benzodiazepines. FRISIUM should not be administered to individuals prone to drug abuse.

• In case of physical dependence, do not do abrupt discontinuation! >>> May lead to withdrawal symtoms >>> include headaches, insomnia, sleep disturbances, increased dreaming, restlessness, tension, mental impairment, confusion, extreme anxiety, excitability, irritability, nervousness, agitation, derealization, depersonalization, hallucinations and symptomatic psychoses (e.g. withdrawal delirium), numbness and tingling sensations in the extremities, muscle pain, tremors, sweating, diarrhea, abdominal cramps, vomiting, nausea, hyperacusis, hypersensitivity to light, noise and physical contact, convulsions, as well as epileptic seizures.

6. Caution for rebound phenomenon: The rebound phenomenon is characterized by a recurrence in enhanced form of the symptoms, which originally led to FRISIUM treatment (i.e. seizures). This may be accompanied by other reactions including mood changes, anxiety, or sleep disturbances and restlessness.

7. Clobazam is contraindicated in biliary, hepatic and pancreatic dysfunction >>> Do low initial doses and gradual dose increments under careful observation!

8. Monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants.

9. Caution for Suicidal Ideation and Behaviour in use of Clobazam! >>> Do a close observation in patient with major depressive disorder.

10. Clobazam or its active metabolite, N-desmethylclobazam, is dialyzable. In long-term treatment, renal function must be checked regularly.

11. FRISIUM can cause respiratory depression >>> caution inpatients with bronchial asthma/ Chronic obstructive pulmonary disorder/ brain damage.

12. Caution for Serious skin reactions >>> Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) >>> closely monitor the patients!

13. Attention: If Clobazam is administered for repeated cycles of therapy, periodic blood counts and liver, renal and thyroid function tests are advisable. (CBC, BUN, Cr, NA K, LFT, TSH)

14. Lithium: Mutually potentiating effect >>> Special precaution is necessary

15. Narcotic Analgesics: Possible euphoria may be enhanced >>> Special precaution is necessary

16. Muscle relaxants and nitrous oxide >>> The effects may be enhanced >>> Special precaution is necessary

17. Overdosage:

 Symptoms:

• Sedation, somnolence, confusion, impaired, coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest.

Treatment:

• Continuous monitoring of vital signs including EKG immediately.
• Immediate attention should be given to the maintenance of an adequate airway and support of ventilation.
• Cardiopulmonary resuscitation may be required
• Flumazenil (Benzodiazepine antagonist –Specific antidote) >>> 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr (contact your regional Poison Control Centre for more information)